Many cigarette smokers report that smoking helps them stay alert and improves their concentration. But does tobacco use confer a general cognitive advantage to smokers or do smokers perceive a boost in performance because nicotine can reverse transient cognitive deficits due to brief (between cigarettes) or prolonged (overnight) periods of tobacco abstinence? Our research in this area has attempted to answer this fundamental question: how does smoking or nicotine affect human cognition? In several studies, we demonstrated that tobacco abstinence can impair cognitive functioning and that, in general, smoking or nicotine reverses such deficits to smoking baseline levels. These data strongly suggest that this is one mechanism that functions to maintain smoking in nicotine-dependent individuals. However, determining whether smoking or nicotine can truly enhance cognition, rather than simply provide withdrawal relief, can be difficult in smokers. Thus, we conducted two studies in which we administered nicotine gum to nonsmokers. The data from both studies were consistent in finding no cognitive enhancing effects of nicotine. The data do not support the hypothesis that nicotine-induced cognitive enhancement contributes to the reinforcing effects of tobacco use during the early stages of nicotine dependence. We have also begun to explore the brain regions activated during performance of cognitive tests and the effect of nicotine on brain activation. In one study, we used PET imaging to measure cognitive activation during a working memory test in smokers, who abstained from smoking for 12 hours, and ex-smokers. At one session, subjects received placebo gum, and at another session, they received 4 mg nicotine gum before performing the memory test and the brain scan. Compared to placebo, nicotine reduced errors on the memory test in smokers, but had no effect on test performance in ex-smokers. The brain regions activated by the memory test were consistent with those reported in the literature: dorsolateral prefrontal cortex, anterior cingulate gyrus, and inferior parietal cortex. When nicotine was administered, brain activation was enhanced in ex-smokers, but reduced in smokers, perhaps reflecting chronic tolerance. In an ongoing study, we are using functional magnetic resonance imaging (fMRI) to investigate changes in brain activity and cognitive abilities during 8 days of tobacco abstinence, continued smoking, or smoking denicotinized cigarettes. This will allow us to determine whether withdrawal effects are due to the absence of tobacco (abstinence condition) or the absence of nicotine (denicotinized cigarette condition).